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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

ABSTRACT: Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the novelty of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n=43) patient cohort to date identified that hypotonia and congenital heart defects are novel prominent features. Both missense variants and putative loss-of-function variants resulted in slow growth in patient derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wildtype littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA-sequencing of patient lymphoblasts and Kmt5b-haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified novel pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems. 

ORGANISM(S): Mus musculus

PROVIDER: GSE184953 | GEO | 2023/01/01

REPOSITORIES: GEO

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Project description:Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across 3-5 chromosomes. Two mothers did not show any phenotypic malformations, although 3-13 protein coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy number changes in two children. This resulted in gene dosage changes, which are likely responsible for their severe congenital phenotypes. In contrast, one child with severe congenital disease, carried all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals strongly affects reproduction and is expected to substantially increase the risk of spontaneous abortions and severe congenital disease. We analyzed one patient-parent-mother's parents quintet (case 1) and a patient-siblings-parent quintet (case 2) with Illumina beadchip arrays and one patient-parent trio (case 3) to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients. Here, we analyzed one patient-parent-mother's parents quintet to test for (de novo) copy number variants and to analyze the parental origin of the complex rearrangements in these patients.

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

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